Glioma is the most aggressive primary brain tumor and is notorious for resistance to chemoradiotherapy. Although its associated mechanisms are still not completely understood, Notch signaling, an ...evolutionarily conserved pathway, appears to be the key processes involved. Nevertheless, its mechanisms are sophisticated, due to a variety of targets and signal pathways, especially microRNA. MicroRNAs, which are small noncoding regulatory RNA molecules, have been proposed as one of the key mechanisms in glioma pathogenesis. Among the known glioma associated microRNA, microRNA‐129, microRNA‐34 family, and microRNA‐326 have been shown to influence the progress of glioma through Notch signaling. Evidence also indicates that recurrence is due to development or persistence of the glioma stem‐like cells and active angiogenesis, which are tightly regulated by a variety of factors, including Notch signaling. In this review, we summarize the recent progress regarding the functional roles of Notch signaling in glioma, including Notch ligand, microRNA, intracellular crosstalk, glioma stem‐like cells and active angiogenesis and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for glioma.
Notch signaling and its ligands act as an oncogene in glioma; microRNAs influence the progress of glioma through Notch signaling; a combination of chemoradiotherapy and disruption of Notch signaling might be a new method of glioma therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Acute myeloid leukaemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. 4‐Amino‐2‐trifluoromethyl‐phenyl retinate (ATPR), a novel all‐trans retinoic acid (ATRA) ...derivative designed and synthesized by our team, has been proven to show superior anticancer effect compared with ATRA on various cancers. However, its potential effect on AML remains largely unknown. Lactate dehydrogenase B (LDHB) is the key glycolytic enzyme that catalyses the interconversion between pyruvate and lactate. Currently, little is known about the role of LDHB in AML. In this study, we found that ATPR showed antileukaemic effects with RARα dependent in AML cells. LDHB was aberrantly overexpressed in human AML peripheral blood mononuclear cell (PBMC) and AML cell lines. A lentiviral vector expressing LDHB‐targeting shRNA was constructed to generate a stable AML cells with low expression of LDHB. The effect of LDHB knockdown on differentiation and cycle arrest of AML cells was assessed in vitro and vivo, including involvement of Raf/MEK/ERK signalling. Finally, these data suggested that ATPR showed antileukaemic effects by RARα/LDHB/ ERK‐glycolysis signalling axis. Further studies should focus on the underlying leukaemia‐promoting mechanisms and investigate LDHB as a therapeutic target.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The pyroptosis is a causative agent of rheumatoid arthritis, a systemic autoimmune disease merged with degenerative articular cartilage. Nevertheless, the precise mechanism of extracellular acidosis ...on chondrocyte pyroptosis is largely unclear. Acid‐sensing ion channels (ASICs) belong to an extracellular H+‐activated cation channel family. Accumulating evidence has highlighted activation of ASICs induced by extracellular acidosis upregulate calpain and calcineurin expression in arthritis. In the present study, to investigate the expression and the role of acid‐sensing ion channel 1a (ASIC1a), calpain, calcineurin, and NLRP3 inflammasome proteins in regulating acid‐induced articular chondrocyte pyroptosis, primary rat articular chondrocytes were subjected to different pH, different time, and different treatments with or without ASIC1a, calpain‐2, and calcineurin, respectively. Initially, the research results showed that extracellular acidosis‐induced the protein expression of ASIC1a in a pH‐ and time‐dependent manner, and the messenger RNA and protein expressions of calpain, calcineurin, NLRP3, apoptosis‐associated speck‐like protein, and caspase‐1 were significantly increased in a time‐dependent manner. Furthermore, the inhibition of ASIC1a, calpain‐2, or calcineurin, respectively, could decrease the cell death accompanied with the decreased interleukin‐1β level, and the decreased expression of ASIC1a, calpain‐2, calcineurin, and NLRP3 inflammasome proteins. Taken together, these results indicated the activation of ASIC1a induced by extracellular acidosis could trigger pyroptosis of rat articular chondrocytes, the mechanism of which might partly be involved with the activation of calpain‐2/calcineurin pathway.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Necroptosis, a necrotic cell death pathway regulated by receptor interacting protein (RIP) 1 and 3, plays a key role in pathophysiological processes, including rheumatoid arthritis (RA). However, ...whether necroptosis is involved in RA articular cartilage damage processes remain unclear. The aim of present study was to investigate the dynamic changes in arthritic chondrocyte necroptosis and the effect of RIP1 inhibitor necrostatin-1 (Nec-1) and acid-sensing ion channels (ASICs) inhibitor amiloride on arthritic cartilage injury and acid-induced chondrocyte necroptosis. Our results demonstrated that the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein phosphorylation (p-MLKL) were increased in adjuvant arthritis (AA) rat articular cartilage in vivo and acid-induced chondrocytes in vitro. High co-expression of ASIC1a and RIP1 showed in AA rat articular cartilage. Moreover, Nec-1 and amiloride could reduce articular cartilage damage and necroinflammation in AA rats. In addition, acid-induced increase in necroptosis markers RIP1/RIP3 were inhibited by Nec-1, ASIC1a-specific blocker psalmotoxin-1 (PcTx-1) or ASIC1a-short hairpin RNA respectively, which revealed that necroptosis is triggered in acid-induced chondrocytes and mediated by ASIC1a. These findings indicated that blocking ASIC1a-mediated chondrocyte necroptosis may provide potential therapeutic strategies for RA treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Objective The aim of present study was to test the hypothesis that activation of receptor for advanced glycation end products (RAGE) pathway contributes to aortic remodeling and endothelial ...dysfunction in sinoaortic denervated (SAD) rats. Methods and results Experiment 1 : 8 weeks after sinoaortic denervation, aortas were removed for measurement of AGE/RAGE pathway. Sinoaortic denervation in rats resulted in enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE in aortas. Experiment 2 : 5 weeks after sinoaortic denervation, the rats received intraperitoneal injections of 500 μg soluble RAGE (sRAGE) daily for 3 weeks. Treatment of SAD rats with sRAGE attenuated aortic remodeling, marked by reduction in AW/length, wall thickness, proliferation of SMC, and collagen deposition, and improvement of endothelial function. Treatment of SAD rats with sRAGE abated aortic oxidative stress, marked by reduction in formation of malondialdehyde, reactive oxygen species, superoxide, peroxynitrite and 3-nitrotyrosine, and enhancement of ratio of GSH/GSSG. Treatment of SAD rats with sRAGE attenuated aortic mitochondrial dysfunction. Treatment of SAD rats with sRAGE suppressed aortic NFκB nuclear translocation and inflammation. Treatment of SAD rats with sRAGE restored aortic NO formation through upregulating eNOS and dimethylarginine dimethylaminohydrolase-2 and downregulating protein arginine methyltransferase-1. Conclusion Activated RAGE contributed to aortic remodeling and endothelial dysfunction in SAD rats, possibly via induction of oxidative stress and inflammation, impairment of mitochondrial function, and reduction in NO bioavailability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
To investigate the clinical experiment of cortical screw in the treatment of tibiofibular syndesmosis separation together with ankle fractures.
From March 2008 to May 2012,42 patients with ...tibiofibular syndesmosis separation were treated with cortical screw, including 20 cases in the left and 24 cases in the right. All the patients had closed injury. According to Lauge-Hansen classification, there were 18 cases of supination-external rotation, in which 4 patients with injuries belong to type II, 8 patients with injuries belong to type III, 6 patients with injuries belong to type IV; 14 cases of pronation-external rotation, in which 6 patients with injuries belong to type III, 8 patients with injuries belong to type IV; and 12 cases of pronation-abduction, in which 4 patients with injuries belong to type II, 8 patients with injuries belong to type III. According to injury of ankle, 4 patients had injuries in one ankle, 28 patients had injuries in 2 ankles, and 12 patients had injuries in 3 ankles. All the pati
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•Ferroptosis existed in ATPR treatment of AML.•ATPR-induced ferroptosis is relied on the autophagy.•Autophagy triggered ATPR-induced ferroptosis by regulating iron homeostasis, ...especially Nrf2.•Targeting iron homeostasis induces ATPR-induced AML cell differentiation.
Ferroptosis, a newly discovered form of non-apoptotic cell death, is induced by an excessive degree of iron-dependent lipid peroxide. ATPR, a novel all-trans retinoic acid (ATRA) derivative, has been extensively developed to show superior anticancer effect than ATRA in acute myeloid leukemia (AML). However, whether ferroptosis exists during ATPR treatment of AML remains unclear. Herein, we found that ferroptosis occurred in an AML xenograft mouse model of ATPR treatment. In vitro, ATPR was verified to induce ferroptosis in a dose-dependent manner by proferroptotic protein marker, lipid peroxidation, and lipid ROS, which could be significantly reversed by ferrostatin-1. Using lysosomal inhibitor chloroquine and iron chelator desferrioxamine, we further revealed that ATPR-induced ferroptosis was regulated by autophagy via iron homeostasis, especially Nrf2. Furthermore, targeting ferroptosis contributes to ATPR-induced AML differentiation. In conclusion, these results indicated that ferroptosis play an important role in ATPR-induced differentiation, and suggested that ATPR would provide a potential therapeutic value for AML treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The objective of this meta-analysis was to evaluate the efficacy and safety of tranexamic acid (TXA) in shoulder arthroplasty (SA).
Academic articles were identified from the Cochrane Library, ...Medline (1966-2017.2), PubMed (1966-2017.2), Embase (1980-2017.2), and ScienceDirect (1966-2017.2). Randomized controlled trials (RCTs) and non-RCTs studying TXA in SA were included. Two independent reviewers conducted independent data abstraction. The I statistic was used to assess heterogeneity. Fixed- or random-effects models were used for meta-analysis.
Two RCTs and 2 non-RCTs met the inclusion criteria. This meta-analysis found significant differences in postoperative hemoglobin reduction (MD = -0.71 g/dL), drainage volume (MD = -133.21 mL), and total blood loss (MD = -226.82 mL) between TXA groups and controls. There were no significant differences in blood transfusion requirements, operation time, or length of hospital stay.
The use of TXA in SA decreases postoperative hemoglobin reduction, drainage volume, and total blood loss and does not increase the risk of complications. Because of the limited high-quality evidence currently available, additional randomized controlled trials are required.
Myelodysplastic syndromes (MDS) are a varied set of hematologic neoplasms and a high risk of progression to acute myeloid leukemia (AML). 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel ...all-trans retinoic acid (ATRA) derivative, play an important role in various types of cancer cells as a tumor inhibitor. However, little is known concerning its antitumor effect on MDS. The cell viability and the percentage of apoptotic cells were used to measure MTT, Flow Cytometry and Hoechst 33342/PI staining. In addition, real-time quantitative RT-PCR (qRT-PCR) and western blotting were used to analyzed the expression of p53, as well as the levels of BNIP3, apoptosis proteins of Caspase-3, BAX and BCL-2. After SKM-1 cells were incubated with DAC, ATRA and ATPR, the viability of the SKM-1 cells was inhibited in a dose- and time-dependent manner. Both Hoechst staining and flow cytometry showed the apoptosis of SKM-1 cells was increased. Moreover, SKM-1 cells treated with ATPR unveiled elevated mRNA and protein levels of p53, BNIP3, BAX and Caspase-3 expression and decreased BCL-2 expression. However, silencing p53 suppressed the pro-apoptosis function of ATPR. Consequently, these data provide the first evidence for ATPR increased apoptosis in SKM-1 cells by p53 that is mutually dependent on and obligatorily linked to BNIP3 gene activation.
•DAC, ATRA and ATPR inhibited the metabolic activity of SKM-1 Cells.•DAC, ATRA and ATPR induced the apoptosis of SKM-1 Cells.•p53 induced SKM-1 cells apoptosis via BNIP3, BAX, BCL-2 and Caspase-3.•ATPR up-regulated the protein level of p53 and induced SKM-1 cell apoptosis via p53.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The objective of this meta-analysis was to compare the efficacy and safety of minimally invasive plate osteosynthesis (MIPO) and conventional plate osteosynthesis (CPO) for humeral shaft fracture.
...Potential academic articles were identified from the Cochrane Library, Medline (1966-2016.3), PubMed (1966-2016.3), Embase (1980-2016.3), and ScienceDirect (1966-2016.3). Gray studies were identified from the references of the included literature. Randomized controlled trials (RCTs) and non-RCT involving MIPO and CPO for humeral shaft fracture were included. Two independent reviewers performed independent data abstraction. I statistic was used to assess heterogeneity. Fixed or random effects model was used for meta-analysis.
Two RCTs and 3 non-RCTs met the inclusion criteria. There was a lower incidence of iatrogenic radial nerve palsy in patients with MIPO (P = 0.006). There was no statistically significant difference in in the risk of developing nonunion, delay union, malformation, screw loosening, infection, operation time, UCLA, and MEPS function score between the 2 groups.
MIPO decreased incidence of iatrogenic radial nerve palsy and is an efficacy and safety technique for humeral shaft fracture. Due to the limited quality and data of the evidence currently available, more high-quality RCTs are required.
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